AU600403B2 - Process for preparing 2 beta-substituted-methylpenicillin derivatives - Google Patents
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- AU600403B2 AU600403B2 AU30290/89A AU3029089A AU600403B2 AU 600403 B2 AU600403 B2 AU 600403B2 AU 30290/89 A AU30290/89 A AU 30290/89A AU 3029089 A AU3029089 A AU 3029089A AU 600403 B2 AU600403 B2 AU 600403B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/06—Preparation by forming the ring or condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A process for preparing a 2 beta -substituted-methylpenicillin compound of the formula <CHEM> wherein -N Y is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and R1 is a penicillin carboxyl protecting group, the process comprising reacting an azetidinonedisulfide compound of the formula <CHEM> wherein R1 is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogen-containing heterocyclic compound of the formula <CHEM> wherein <CHEM> is as defined above in the presence of a metal compound. n
Description
AUSTRALIA
PATENTS ACT 1952 Form COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: SComplete Specification-Lodged: Accepted: Lapsed: Published: "This document cont~ii she t Priority: amendments mode :ndcir Section 9 aid s tect for Related Art: pa TO BE COMPLETED BY APPLICANT Name of Applicant: 1) TAIHO PHARMACEUTICAL COMPANY, LIMITED Address of Applicant: 1-27, KANDANISHIKI-CHO
CHIYODA-KU
TOKYO-TO
JAPAN
2) OTSUKA KAGAKU KABUSHIKI KAISHA Address or Applicant: 10, BUNGO-MACHI, HIGASHI-KU OSAKA-SHI, OSAKA-FU
JAPAN
Actual Inventor: Address for Service: GRIFFITH HACE CO,, 601 St. Kilda Road, Melbourne, Victoria 3004, Australia.
Complete Specification for the invention entitled: PROCESS FOR PREPARING 2 -SUBSTITUTED- METHYLPENICILLIN DERIVATIVES The following statement is a full description of this invention including the best method of performing it known to me:la PROCESS FOR PREPARING 28-SUBSTITUTED-METHYL- PENICILLIN DERIVATIVES The present invention relates to a novel process for preparing a 28-substituted-methylpenicillin derivative and more particulary to a process for preparing a 28o"o substituted-methylpenicillin derivative by introducing a o0 o0o 2 nitrogen-containing heterocyclic group to the 2e-methyl
OQO
or group.
ao o0" The 28-substituted-methylpenicillin derivative 0 0 produced by the process of the invention is represented by the formula 0000 0 00 o
ICH
3 0 N (1) 0
COOR
1 00 O0 0 wherein -NY is an optionally substituted heterocyclic 0 group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and R 1 is a penicillin carboxyl protecting group.
The compound of the formula is useful as the intermediate for preparing a 28-substituted-methylpenicillin 1,1-dioxide compound having a potent 8lactamase inhibitory activity and represented by the formula 2 0 0 S N SCH3 N C (II) 0 COOR 2 wherein -N Y is as defined above and R 2 is a hydrogen atom or a penicillin carboxyl protecting group that can be readily metabolized or hydrolyzed in vivo to give a free carboxyl group.
S' Of the compounds of the formula those S" wherein -N is an optionally substituted 1,2,3-triazol- 1-yl group are known and processes for preparing such compounds are disclosed in U.S. Patents No.4,529,592, o 0 °o No.4,562,073, No.4,668,514 and J. Med. Chem., Vol. o0o 1469 (1987). The disclosed processes are conducted in the 0 0 0 0 following manner.
00 o 0 0 0 0 00 0--
NU
Step A Step B
N-
COOl?
NCH
3
COOR
1 (2)
(MI)
(1) Step C 0 t- 0
N
3 N~
CH
3 0 COOlI Step D 0 0 N X N
CH
3
R
3 COOl? 2 (4) (3) i 1 4 a ca a 1) a a~ a0 a Dc0 a a 0i 0 )9 au a o a a I a a) a a o a D o a a aa 00 t a ar In the foregoing formulas, R is a substituted or unsubstituted heterocyclic group, R 1 and R2 are as defined above, R 3 and R4 are various substituents such as those disclosed in the foregoing U.S. patents and X is a halogen atom.
In the foregoing reaction scheme, the azetidinonedisulfide compound (III) is converted in step A to a 20-halogenomethylpenicillin compound which is then converted to an azide compound in step B. The azide compound is then oxidized in step C to give an azide 1,1-dioxide compound which is further reacted in step D with an acetylene derivative which can react with the compound to give a compound having a substituted or unsubstituted 1,2,3-triazol-l-yl group.
However, said process for preparing 1,2,3triazol-l-yl componds is useful only for introducing substituted or unsubstituted 1,2,3-triazol-l-yl groups and is not useful for introducing various other types of heterocyclic groups to the 2B-methyl group of the penicllin derivatives. Furthermore, the above process has the disadvantage of necessitating a number of reaction steps and giving the desired compound in a low yield.
Additionally, the process invariably forms as an intermediate the 28-halogenomethylpenicillin compound (1) which is not stable and requires a cumbersome handling, ~~-nlYP~I~_ 5 and also requires the use of azide compound and acetylene derivative which have the danger of explosion and therefore should be used in small amounts with due safety measure. Thus the above prior art process is not commercially advantageous.
An object of the invention is to provide a commercially advantageous process by which a wide variety of heterocyclic groups can be introduced into the 28methyl group of penicillin compounds with a minimal number of reaction steps and without necessitating the use of dangerous reactants.
This invention provides a process for preparing S"a 28-substituted-methylpenicillin derivative represented by the formula NCH3 N
(I)
0 COOR 1 wherein -N Y is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and R 1 is a penicillin carboxyl protecting groups the process comprising reacting an azetidinonedisulfide compond of the formula 1 I ii i L LUrllZ 6-
S-S-R
S N I (III)
COOR
1 wherein R1 is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogencontaining heterocyclic compound of the formula H-N
(IV)
wherein -N Y is as defined above in the presence of a metal compound.
We have conducted an intensive research on the S, reaction of an azetidinone derivative and a nitrogencontaining heterocyclic compound. As the result, we found a versatile process capable of introducing various types of heterocyclic groups selectively into the 2p-methyl group of penicillin derivatives. The present invention has been accomplished based thereon.
The process of the invention requires only one step to produce the compound of the formula which in turn can be easily oxidized, thereby producing the above B-lactamase inhibitory compound of the formula (II) in a good yield. The process of the invention can be conducted -7 with simple procedure without requiring the use of dangerous reactants, and hence is commercially advantageous.
Penicillin carboxyl protecting groups represented by R 1 include known carboxyl protecting groups which are conventionally used in the synthesis of penicillins, and examples thereof are described in Japanese Unexamined Patent Publication No.49-81380 and in tCephalosporins and Penicillins, Chemistry and Biology" edited by E. Flynn published in 1972 by Academic Press. Preferable examples of the group R, are methyl, ethyl, propyl, butyl, tert-butyl, l,l-diniethylpropyl, 1cyclopropylmethyl, 2-cyano-l,l--dimethylethyl, bromobenzoylmethyl, p-nitrobenzoylmethyl, dimethylaininomethyl, methylthiorm-thyl, pilenylthiomethyl, succinimidomethyl, trichloroethyll tribromoethyl, 1,1dimethyl-2-propenyl, 1,3-dimethyl-3-buteniyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, di(p-methoxyphenyl)methyl, acetoxyrnethyl, acetoxyethyl, propionyloxyethyl, 2.,lyoxmthl pivaloyloxyethyl, pivali-yloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, methoxymethyl, ethoxymethyl, benzy2.oxymethy., 3phthalidyl, crotonolacton4-yl, tetrahydropyrany., dimethylch2.orosilyl, trichlorosilyl,l pydidine-l-oxide-2- -8 methyl, quinoline-l-oxide-2-methyl and the like.
The heterocyclic group represented by R is a substituted or unsubstituted 5- or 6-inembered heterocylic group which contains 1 to 4 nitrogen atoms and may further contain one oxygen or sulfur atom as the heteroatom in the ring structure and which may optionally be fused with a benzene ring. Examples of the 5- or 6-meinbered heterocyclic group include pyrrolidinyl, piperazinyl, piperidyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, thiazolyl, thiadiazolyll thiatriazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, triazolyl, tetrazolyl and the like. These heterocyclic groups may optionally have 1 to 3 substituents. The substituents include l4 alkyl groups aur~h as methyl, ethyl, propy. and butyl, C 1
C
4 alkoxy groups such as rnethoxy, ethoxy, propoxy and butoxy, halogen atoms such as fluorine, chlorine and bromine, nitrof aryl groups such as phenyl, tolyl and xylyl, aralkyl groups such as benzyl, phenethyl and trityl. Preferable examples of the heterocyclic group represented by R are benzothiazol-2-yl, 2-quinolyl, 2pyridy,, 3-pyridyl, l,3-thiazol-2-yl, l,3,4-thiadiazol-2yl, 2,3,4,5-thiatriazol-2-yl, l,3-oxazol-2-yl, 1,3,4oxadiazol-2-yl, 2,3,4,5-oxatriazol-2-yl, 1-methylimidazol- 2-'y3, l-methylbenzimidazo.-2-yl, benzoxazoJ.-2-yl, I- -9- 5-methyl-1,3, 4-thiadiazol-2-yl, 4iethyl-thiazol-2-yl and the like, among which the most preferred is benzothiazol-2--yl.
Examples of optionally substituted heterocyclic groups containing 2 to 4 nitrogen atoms as the heteroatom in the ring structure and represented by are substituted or unsubstituted monocyclic or bicyclic heterocyclic groups only containing 2-4 nitrogen atom5 as the hetero atom in the ring structure, such as pyrazolyl, benzotriazolyl, benipyrazolyl, benzirnidazolyl and the like. Preferable examples thereof are pyrazol-l-yl, l,2,4-triazol-1-yl, l,2,4-triazol-4-yl, tetrazol-l-yl, tetrazol-2-yl, benzotriazol-l-yl, benzpyrazol-l-yl, benzimidazol-l-yl and the like. These heterocyclic groups may optionally have 1 to 3 substituents, which include C 1
C
6 straight- or branched-chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butylf sec-butyl, tertbutyl, pentyl and hexyl; Cl-C 6 straight- or branched-chain alkoxy groups such as methoxy, ethoxy, propoxy, butoxy and tert-butoxy; C 2
-C
6 acyl groups such as acetyl, propionyl and butyryl; carbamoyl group; C 1
-C
6 alkyl-substituted carbamoyl groups such as inethylcarbamoyl, ethy]lcarbamoyl, propylcarbamoyl, butylcarbanoyl, pentylcarbainoyl, 10 isopropylcarbamoyl and tert-butylcarbamoyl; halogen atoms such as fluorine, chlorine, bromine and iodine; hydroxyl group; trifluoromethyl group; nitro group; amino group; formyl group; C 1
-C
6 alkoxy-Cl-C 6 alkyl groups such as methoxymethyl, ethoxymethyl, propyloxyrnethyl, butoxymethyl, mef-hoxyethyl, ethoxyethyl, propyloxyethyl and butoxyethyl; C 2 -C 7 a2koxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl; C 3
-C
7 alkenyloxycarbonyl groups su..,h as 1-propenyloxycarbonyl and 1-butenyloxycarbonyl; benzyJloxycarbonyl groups which may optionally have 1-3 substituents seleted from the group consisting of Calkyl group, a halogen atom such as fluorine, chlorine or bromine and nitro group on the benzene ring, such as benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, pnitrobenzyloxycalrbonylf m-nitrobenzyloxycarbonyl, pchlorobenzyloxycarbonyl, m-chlorobenzylQxycarbonyl, ofluorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, omethylbenzyloxycarbonylo p-ethylbenzyloxycarbonyl, mpropylbenzyloxycarbonyl, 4-nitro-2-ethylbenzyloxycarbonyl, 2,4-dinItrobenzyloxycarbonyl, 2,4,6-trinitrobenzyloxycarbonyl, 2,4-dimethylbenzyJloxycarbonyl and 2,4,6triethylbenzyloxycarbonyl; phenyl groups which may 11 optionally have 1-3 substituents selected from the group consisting of C 1
-C
6 alkyl group, CQ-C 6 alkoxy group and a halogen atom including fltorine, chlorine or bromine on the benzene ring, such as phenyl, tolyl, xylyl, 2-ethylphenyl, 4-ethylphenyl, 2,4,6-trimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-dichlorophenyl, 4-fluorophenyl and 4-bromophnyl. C 1
-C
6 alkyl groups substituted with 1-3 phenyl groups such as benzyl, phenylethyl, diphenylmethyl and trityl; Cl-C 6 alkylthio groups such as methylthiof ethylthio, propylthio and isopropylthio; C 1
-C
6 alkylsulfinyl groups such as methylsulinyl, ethylsulfinyl, propy1sulfinyl and isopropylsulfinyl; C -C 6 alkyLsulfonyl groups such as methylsulfonyl, othylsulfonyl, propylsulfonyl and isopropylsulfonyl and the like.
The compounds of the formula (III) used as the starting material in the process of the invention are known and described, for example, in U.S. Patent No.
4,518,533, Japanese Unexamined Patent Publications No. 243064 and No. 62-242660 and can be prepared by known processes disclosed in these publications.
The metal compound useful in the process of the invention includes various salts or oxides of heavy metals such as silver, cerium, copper, lead, mercury, thallium and the like. Preferable examples of the heavy metal I 12 salts are heavy metal salts of an organic carboxylic acid, especially C 2
-C
4 fatty acid such as acetic acid, and include copper acetate, lead acetate, silver acetate, mercury acetate, mercury (II) acetate, cerium acetate and the like. Also usable as the salt are carbonates of such heavy metals, such as silver carbonate, copper carbonate and the like. Preferable examples of the oxides of heavy metals are mercury oxide, copper oxide, lead oxide, silver oxide and the like. It is important to conduct the reaction in the presence of the metal compound. If the metal compound is not used, the desired compound of the formula can not be obtained.
The process of the invention i° usually conducted as follows. The azetidinonedisulfide compound of the formula (III) is reacted with the compound of the nitrogen-containing h-terocyclic compound of the formula (IV) in the presence of a metal compound in a suitable solvent. The nitrogen-containing heterocyclic compound of thie formula (IV) is used in an amount of about 2 to moles, preferably about 5 to about 10 moles, per mole of the compound of the azetidinonedisulfide compound of the formula (III). The metal compound is used in an amount of about 1.5 to 5 moles, preferably about 2 to 3 moles, per mole of the azetidinonedisulfide compound of the formula (711). The solvent to be used is not particularly limited i 1 _j _Y I I iyll_ _Llli 13 insofar as it does not adversely affect the reaction and includes, for example, an organic solvent such as acetonitrile, nitromethane, methyl ethyl ketone or the like, and a mixture of such organic solvent and water.
The reaction is usually conducted at a temperature of about 20 to about 100 OC, preferably about 50 to about The reaction pressure is not critical. The reaction is preferably conducted under atmospheric pressure. It is preferable to conduct the reaction in an atmosphere of an inert gas such as argon gas, nitrogen gas and the like.
The reaction is continued until the starting material is consumed and is usually completed within about 0.5 to 24 hours. After the completion of the reaction, the desired compound of the formula can be isolated and purified by a conventional method such as recrystallization, column chromatography and the like.
The compounds of the formula prepared by the process of the invention are useful as intermedeiate for synthesizing the F-lactamase inhibitors of the formula The 8-lactamase inhibitor of the formula (II) can be prepared from the compound of the for-ula for example, by oxidizing the compound of the formula The oxidation reaction is usually conducted in a solvent using a conventional oxidizing agent such as permanganic acid, potassium permanganate, periodic acid, peracetic 14 acid, trifluoroperacetic acd, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide or the like. The oxidizing agent may be used in excess, but may preferably used in an amount of about 1 to 5 moles per mole of the compound of the formula The solvent can be any solvent which does not affect the oxidation reaction and includes dichloromethane, chloroform, carbon tetrac-loride, pyridine, tetrahydrofuran, dioxane, acetone, formic acid, dimethylformamide, ethyl acetate, water and the like. The reaction temperature is not particularly limited but generally about 0 to about
OC.
If desired, the compound of the formula (II) thus prepared may be subjected to a conventional reaction for changing the carboxyl protecting group to a carboxyl protecting group which can be readily metabolized in vivo or to a conventional de-esterification reaction for changing the carboxyl protecting group into a free acid form. Such reactions are described, for example, in "Design of prodrugs", pages 3-6, edited by Hans Bundgaard, S1985, Elsevier Science Publishers B.V. (Biological Division).
The process of the present invention is described in greater detail with reference to the following examples. Reference Example 1 below illustrates 15 the oxidation of the desired compound of the formula (I) to a B-lactamse inhibitor of the formula (II).
Example 1 Preparation of p-methoxybenzyl 2a-methyl-28-(1,2,3triazol-l-yl)methylpenam-3a-carboxylate To 195 mg of p-methoxybenzyl 3-methyl-2-(2-oxo- 4-(benzothiazol-2-yl)dithioazetidin-l-yl}-3-butenoate were added 210 mg of mercury acetate (content 282 mg of iH-l,2,3-triazole and 3 ml of acetonitrile, and the mixture was heated with stirring under argon atmosphere at a bath temperature of 70 OC for 6 hours. The reaction mixture was allowed to cool and was filtered on a Celite filter followed by washing the filter with dichloromethane. The resulting filtrate was washed with an aqueous solution of sodium bicarbonate. The organic layer separated was dried over sodium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: benzene-ethyl acetate giving 114.8 mg of p-methoxybenzyl 2a-methyl-26-(l,2,3-triazol-li yl)methylpenam-3a-carboxylate as an oil. Yield: 74%.
Infrared absorption spectrum (neat) max(cm- 1 1775, 1735 Nuclear magnetic resonance spectrum (CDC1 3 6 (ppm) L 16 1.34 (3H, s) 3.03, 3.53 (2H, AB-X, J=l6Hz, J=2Ez, J=4Hz), 3.78 OHE, 4.58 (2H, 4.74 (1Hi, 5.09 (2H, s) .9(1H, dd, J=4, 2Hz), 6.83 (2,Hp d, J=811z), 7.26 (2H, d, J=8Hz), 7.68 (2H1, mn) Example 2 Preparation of p-methoxybenzyl 2a-methyl-2p-(l,2,3triazol-l-yl )methylpenam-3a-cazboxylate To 176 mng of p-methoxybenzyl 3-methyl-2-{2-oxo- 4- (pyridin-2-yl )dithioazetidin-1-.yl)-3-butenoate were added 219 mg of mercury acetate (content 282 ing of 11-1,2,3-triazole and 2 ml of acetonitrile, and the mixture was heated with stirring under argon atmosphere at a bath temperature of 70 OC for 6 hours. The reaction mixture was allowed to cool and was filtered on a Celite filter followed by washing the filter with dichloromethane. The resulting filtrate was washed with an aqueous solution of sodium bicarbonate. The organic layer separated was dried over sodium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: benzene-ethyl acetate giving 78.6 mg of p-'methoxybenzy2. 2a-mehyl-2-(,2,3-triazol-lyl)methylpenanl-3ci-carboxylate as an oil. Yield: 56%.
The Infrared absorption spectra (neat) and nuclear magentic resonance spectra (CDC1 3 of the 17 resulting product were identical with those of the produlct of Example 1.
Examples 3-15 Following the general procedure of Example 1 and using the starting material of the formula \III) and reactant of the formula (IV) listed in Table 1 below, the products of the formula and shown in Table 1 were prepared.
Table 1 shows the yields achieved. Table 2 below shows the spectral data of the products obtained.
Examples 16-18 Following the general procedure of Example 1 and conducting the reaction in a different solvent listed in Table 3 at a temperature-of at 70 OC, the product of Example 1 was prepared.
Table 3 shows the yield achieved.
In cables 1 to 3, the abbreviations used therein have the following meaning.
BT benzothiazol-2 yl P 2-pyridyl BO benzoxazol-2-yl MT MTD 5-methyl-1,3,4-thiadiazol-2-yl PMB p-methoxybenzyl 18 PNB p-nitrobenzyl Bh benzhydryl PM 2-pyrimidyl Me methyl o i0 0 0 0 0 0 C,0 00 0 Ta blIe 1 Ex. Compound 'Compoundu Metal Product Yield (II) (IV) compd M%
S-SBT
z N N N 3 N HN N IlgO 5 1 0 COOPIB 0
COOPMB
S-SBT
A-
4 N H NAg~ HN NNg~ o COOPI4BN 0
COOPMB
S-SBT
5 N
N
N1N -N ligOAc 6 8 COOh0' COOBh Ex. Compound Compound Metal Product Yield (IV) compd S-S-P A.k s -N N 6 H N N IlgOAc 39 XN /N CON 0 OOPNB 0_ s N ,,N 1 53 S-SBT "N NCOOMe HN N AgOAc 0 COOlMe o COOPNB MeOOC COOMe \N COOMe 4 3 0 'COOPN3 J~7I E3x. Comipound Comp,)und Metal Product Yield (IV) couipd M%
S-SBO
0
N
0 COOPNB HN "'N MeGOC AgOAc s N Az ,N 0 COOMe
COOPNB
\N COOMe N ~N COOMe 0 N COOPNB 53 71 E. Conipoun. 'Comipound {Metal Product Yield (111)(IV) compd M% s N ~N 26 SN r COOMe 'SSTR N Ce(O"I) 3 0 >COOMe 9 NCOOPNB 0 COOPNB COe COOMe /N OOMe
N
S ~N COOMe 2
;N
0 COOPNB Ex. Compound Compound TMetal Product Yield (II)(IV) compd M% s N AN ,S-S-MTD A.N. COOMe HIN 'N igO 0 COOMe 0 COOPNB ICOO~le
CO
MeOOC N/N-.C COOMe \N COOMe 4 0
N
0 COOPNB f Comipound Comfpound MetiiPrdt (IYid (lii)(IV) compd
M%
s N N 53 N rCOOlle SCOOl~e uIN 'N AgOAc
COOPMB
1 1 -N><eOCCle 0 CO PII ReO C C O~eCOOMe s N\J COOMe 4 1
N
0 'COOPMB S-SBT NNsANNI 12 N L j N HgOAc -46 COOMB Hj ~COOPIAB Ex. Compound Compound Metal Product'(I Yield (IV) Icompd M% 34 N- N 0 COOPMB S-SB]. 11N N ligOAc 13
IN-N
0 %C-OOPM4B s N N
N
0 COOPAB 14 SS]'N figOAc S SSTN I =\NH N COB 0 COOPMB r r Comspound Off1) Compound fIV) Metal o m pd Product I Yield If-SBT XsN
N
IIHN N HgOAc 33 600OPNB 0 COOPNB TablIe 2 Ix.P roduct J R (P.cm) NMR (06, p pm) 3
N,
(identical with Example 1) 4 Nf 0 COOPMB N=.N 1.28(311.s), 3.,3.3.6I(2HAB-X.J=16Hz.
s N ,J=2Hz.J=4Hz), 4.57(2ll.s), 4.8"7(1H.s), 1760O,1740 5.3'(Hdd.J=2.4Hz) 6.87(111,s), N OOhI7.27(1O1s) 7.68(111,s) 4=N 1.40011.0), S.2O 1 3.71(2l.AB-XJ=16FIz.
s N J=211z.J=4Iz>, 4.63(2H~s), 4.9O(Ills), 6 1775,1740 5.27(2H~s), 5.43(1H.dd.J=2.4Hz) 0 COOPNB 25 (211I d. J=91lz) Ex. P roduct J R 0, NMR 03, p pm) s -N N I.38(SH~s), 3.22,3.62(2H 9 AB-XJ=61z 1 7 1785-1735 J=211z.J=411z), 3.99(6I1s), 4.97(211~s),, N coome (broad) 5.I8(1H~s), 5.28(211,s), 5.37(lli, 0 COOMe dd.J=2.41z) 7.53(2ll.d.J=9Hz), 8 COOPNB 8.23(2IJ~d.J=911z) N COOMe I N alCOOMe 17751720 J="-Hz.J=4Hz), 3.97(6H~s), 4.75(2H~s), N 5.23(211,s), .51i~) 5.40(I1 9 s), 0 7.48(2H~d.J=811z\, 8.20(211.d.J=8Hz)
COOPNB
Ex. P roduct J R (p clr') NMR (65, p pm) I.33(3H~s) 3.I6-3.54(2 1 AB-X,J=16Hz, N NN J=2Hz.J=4Hz), 3.8O(3H~s), 3.97(6II1.s), 0 COOIme 5.33(1H~dd, J=.4Hz), 6.92(2H~d.J=8Hz), o XCOO~e 7:28 (211, d. J=811z) N COOMe 1.28(3I 1 8.15,3.59(21.A13-X.J=l6HJz, -N J=2Hz.J=4Hz), 3. 80(3Hs). 3.95(6H~s), N COOMe 1780,1740 4.72(211,s), 5.08(2'11.s), 5.23(1Hi.s), N 5. 32(11,dd. J=2.411z), 6. 83(,2I1d. J=8I-lz), 0 COOPMB '.23(2H,d.J=8Hz) A IINT1.38(3H.s), 3.20.3.51(2H.AB-X.J=l6Hz.
121N NJ=2J1z.J=41Hz), 3.78(3I~s), 4.85(2I-I.s), N12 1775,1740 4.97(1H,s), 0'.10(211,s), 5.33(1H 3 N dd 9 J=2 1 Hz) ,6.82(211,d.J=8Hiz) 0 COOPMB .17(51) (1n) Ex. P roduct IJR cuF' NMR p pm) N=N ,1.33(3H.s), 3.19,3.6I(211.AB-XJ=161z, s N N J=2HzJ=4Hz), -3.82(3I1 3 4.62(2H,s), N J=2.4I1z), 6.93(2II.d.J=8I1z), 7.23(211, o COOPM d.J=811z), 8.75(1H.s) 13 J~N 1.25(3I1.s), 3.15.3.61(2H.AB-X.J=6Jlz.
N J=2Hz.J=4Hiz), 3.78 4.87 (21.s), 1780,1742 5.08(21i~s), 5.23(1i1.s), 5.33(IJI~dd, N J=2.4Hz), 6.82(2H~d.=811z) o COOPM3 7.23(211bdj'=1z), 8.48(1ll~s) N N J=2Hz 1 J=4Hz), 3.80(3H~s), 4.37(211,s), 14 1770,1735 4.93(1IJ~s), 5.10(2H~s), 5.37(I11.dd, N J=2.411z), 6.85,(2l.d.J=811z), 7.23(2H, 0COOPMB d.J=8Hz), 7.93(ll~s)8.12(IH,s) Ex. 1 P roduct JR (i.'cm- 1 NMR p pm) s NT N 1.370(H~s), 3. 13,3.609(2H.AB-X. J=1611z 1 I- 773,1750 J=21Lz.J=4I1z), 4.16(211,s), 4.69(I1 1 s), N 5.22(2H~s). 5.36(IHinY. 7.OI(2H~s), 0j 'COOPNB 7.45(21i 1 7.51(111,s), 8.16(2ll~d) TablIe 3 Ex. Compound (Ml) SolIvent Reaction Reaction Product Yield temp. time
M%
S-SBT S N 16 CH 3
NO
2 70 0 T 6hr \N 69 /N
N
O OP 0 COOPMB 17 SBT070 0 OC 3hr N- 51 N CH 3 CCH 2
CH
3
N
O0PM 0 COOPMB S-SBT
NN
18 C11 3 CN-11 2 0 7 0 0 C 3hr ~N 46 /EN (3 T N 0 %C0O I -33 Reference Example 1 Preparation of p-methoxybenzyl 2a-methyl-2s--(l,2,3triazol1-yl)methylpenam-3ca-carboxylate 1,1-dioxide A 980 mg quantity of p-rnethoxybenzyl 2cz-rethyl- 2p-(l,2,3-triazol-l-yl)methylpenam-3a-carboxylate was dissolved in a mixture of 6 ml of acetone and 2 ml of water, and 3 ml of acetic acid was added to the solution. Then, 814 mg of potassium permanganate was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After addition of 30 hydrogen peroxide until the reaction mixture became colorless, the mixture was extracted with 50 ml of methylene chloride. The methylene chloride layer was evaporated off and the residue was subjected to a silica gel column chromatography (eluent:chloroform-acetone= 19:1), giving 976 mg of the title compound in the form of a foam. Yield: 92%.
Infrared absorption spectrum (KBr) 1 ma (cf 1 1800, 1792, 1760 Nuclear magenetic resonance spectrum (CDCl 3 6 (ppm) 1.20 (3H, 3.50-3.55 (2H, in), 3.82 (3H, 4.55 (1Hi, 4.59-4.66 (1H, in), 5.03 (2H, 5.21 (2H, 6.92 (2H, d, J=8.8Hz), 7.36 (2H, d, J=8B.BHz), 7.72 (lHt d, J=l.lHz), 7.76 (lH, d, J=I.l~z)
Claims (7)
1. A process for preparing a methylpenicillin derivative represented by the formula 1 /S'S N Y N CH 3 0 COOR 1 wherein -N is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and R 1 is a penicillin carboxyl protecting group, the process comprising reacting in azetidinonedisulfide compound of the formula S-S-R o (III) COOR 1 wherein R 1 is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogen- containing heterocyclic compound of the formula H-N Y (IV) wherein -NY is as defined above in theresen ceo a 34a in a solvent and in the presence of a metal compound which is an organic carboxylic acid salt, carbonate or oxide of silver, mercury, cerium, copper, lead or thallium, and wherein the reaction is carried out a temperature of about to 100C. o4 0 0. y o c -metal -omp-a-ml.
2. A process as defined in claim 1 wherein -N O is optionally substituted pyrazolyl, imidazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, benzotriazolyl, benizpyrazolyl or benzirnidazolyl.
3. A process as defined in claim 1 wherein -N O is optionally substituted pyrazol-2,-yl, imidazol-l-y'l, yl, lf2,4-triazol-4-ylf tetrazol-l-yl, tetrazol-2-yl, benzotriazol-l-yl, benzpyrazol-l-yl or benzimidazol-l-yl.
4. A process as defined in claim 1 wherein -q3 is pyrazolyl, imidazolyl, 1,2,3-triazo 4 yl, 1,2,4- triazolyl, tetrazolylf benzotriazolyl, benzpyrazolyl or benzimidazolylt each of which may have I to 3 substituents selected from the class consisting of Cl-C 6 straight- or branched-chain alkyl group, C 1 -C 6 straight- or branched- chain alkoxy group, C 2 -'C 6 acyl group, caxtbamoyl group, Cl- C 6 alkyl-subs t Itubed carbamoyl group, halogen etom, hydroxyl group, trifluoromethyl group, nitro group, amino group, formyl group, CI-'C 6 alkoxy-Cl-C 6 alkyl gtoup,C 2 C alkoxicarbonyl group, C 3 -C 7 alkenyloxycarbonyl group, benzyloxycarbony, group which may optionally have 1-3 substItUents selected from the group consisting of CI-C 6 alkyl group, a halogen atom and nitro group on the benzene ring, phenyl group which may optionally have 1-3 36 substituents selected from the group consisting of CI-C 6 alkyl group, C 1 -C 6 alkoxy group and halogen atom on the benzene ring, C 1 -C 6 alkyl groups substituted with 1-3 phenyl groups, C 1 -C 6 alkylthio group, CI-C 6 alkylsulfinyl group and C 1 -C 6 alkylsulfonyl group.
A process as defined in claim 1 wherein R is a substituted or unsubstituted 5- or 6-membered heterocylic group which contains 1 to 4 nitrogen atoms and may further contain one oxygen or sulfur atom as the heteroatom in the ring structure and which may optionally be fused with a benzene ring.
6. A process as defined in claim 1 wherein thea metal compound is an organic carboxylic acid valt, carbonate or oxide Of silver, mercury, cerium, copper, lead or thalj.um. 6. A process as defined in claim 1 wherein the metal compound is an acetic acid salt, carbonate or oxide of silver; mercury or cerium.
7. A process as defined in claim I wherein the metal compound is mercury oxide, mercury acetate or cerium acetate. S~ A process as defined in claim 1 wherein the metal compound is used in an amount of about 1.5 to moles per mole of the compound of the formula (III). A A process as defined in claim 1 wherein the 37 compound of the formula (IV) is used in an amount of about 2 to 20 moles per mole of the compound of the formuil, (III). A process as defined in claim 1 wherein the reaction is carried out a temperature of about 50 to 70 0 C. DATED THIS 24TH DAY OF MAY 1990 TAIHO PHARMACEUTICAL CO., LTD. and a OTSUKA KAGAKU K.K By its Patent Attorneys: GRIFFITH HACK CO. Fellow Institute of Patent Attorneys of Australia. I
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-49038 | 1988-03-01 | ||
| JP63049038A JP2599610B2 (en) | 1988-03-01 | 1988-03-01 | Process for producing 2β-substituted methylpenicillin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3029089A AU3029089A (en) | 1989-09-07 |
| AU600403B2 true AU600403B2 (en) | 1990-08-09 |
Family
ID=12819915
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU30290/89A Expired AU600403B2 (en) | 1988-03-01 | 1989-02-23 | Process for preparing 2 beta-substituted-methylpenicillin derivatives |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4898939A (en) |
| EP (1) | EP0331394B1 (en) |
| JP (1) | JP2599610B2 (en) |
| KR (1) | KR910001308B1 (en) |
| CN (1) | CN1022836C (en) |
| AT (1) | ATE92492T1 (en) |
| AU (1) | AU600403B2 (en) |
| CA (1) | CA1339124C (en) |
| DE (1) | DE68907953T2 (en) |
| ES (1) | ES2058499T3 (en) |
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| US6897780B2 (en) * | 1993-07-12 | 2005-05-24 | Hill-Rom Services, Inc. | Bed status information system for hospital beds |
| TW200523264A (en) * | 2003-10-09 | 2005-07-16 | Otsuka Chemical Co Ltd | CMPB crystal and method for producing the same |
| TW200519119A (en) * | 2003-10-10 | 2005-06-16 | Otsuka Chemical Co Ltd | PENAM crystal and process for producing the same |
| CN107033161B (en) * | 2017-05-04 | 2019-01-01 | 石家庄万业化工科技有限公司 | A kind of synthetic method of tazobactam |
| WO2021120063A1 (en) * | 2019-12-18 | 2021-06-24 | 凯莱英医药集团（天津）股份有限公司 | Method for continuously synthesizing tazobactam intermediate |
| CN114031629A (en) * | 2021-12-10 | 2022-02-11 | 山东安舜制药有限公司 | Method for synthesizing tazobactam intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin derivatives |
| GB2157286A (en) * | 1984-04-12 | 1985-10-23 | Leo Pharm Prod Ltd | beta -lactum antibiotic potentiators |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4482565A (en) * | 1980-02-22 | 1984-11-13 | Farmitalia Carlo Erba S.P.A. | β-Lactam-containing antibacterial agents and β-lactamase inhibitors |
| JPS58225091A (en) * | 1982-06-21 | 1983-12-27 | Taiho Yakuhin Kogyo Kk | Penicillin derivative and its preparation |
| US4464237A (en) * | 1982-08-09 | 1984-08-07 | Otsuka Kagaku Yakuhin Kabushiki Kaisha | Process for preparing β-lactam derivatives |
| US4562073A (en) * | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
| CA1239392A (en) * | 1983-10-13 | 1988-07-19 | Shigeru Yamabe | Penicillin derivatives and process for preparing the same |
| JPS62294686A (en) * | 1987-05-29 | 1987-12-22 | Taiho Yakuhin Kogyo Kk | Penicillanic acid derivative |
-
1988
- 1988-03-01 JP JP63049038A patent/JP2599610B2/en not_active Expired - Lifetime
-
1989
- 1989-02-23 AU AU30290/89A patent/AU600403B2/en not_active Expired
- 1989-02-27 AT AT89301925T patent/ATE92492T1/en not_active IP Right Cessation
- 1989-02-27 DE DE89301925T patent/DE68907953T2/en not_active Expired - Lifetime
- 1989-02-27 ES ES89301925T patent/ES2058499T3/en not_active Expired - Lifetime
- 1989-02-27 EP EP89301925A patent/EP0331394B1/en not_active Expired - Lifetime
- 1989-02-28 KR KR1019890002436A patent/KR910001308B1/en not_active IP Right Cessation
- 1989-02-28 CA CA000592299A patent/CA1339124C/en not_active Expired - Lifetime
- 1989-02-28 US US07/316,632 patent/US4898939A/en not_active Expired - Lifetime
- 1989-03-01 CN CN89102521A patent/CN1022836C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin derivatives |
| GB2157286A (en) * | 1984-04-12 | 1985-10-23 | Leo Pharm Prod Ltd | beta -lactum antibiotic potentiators |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1339124C (en) | 1997-07-29 |
| DE68907953T2 (en) | 1993-11-18 |
| JP2599610B2 (en) | 1997-04-09 |
| US4898939A (en) | 1990-02-06 |
| EP0331394A1 (en) | 1989-09-06 |
| JPH01224377A (en) | 1989-09-07 |
| ES2058499T3 (en) | 1994-11-01 |
| CN1036767A (en) | 1989-11-01 |
| ATE92492T1 (en) | 1993-08-15 |
| KR910001308B1 (en) | 1991-03-02 |
| AU3029089A (en) | 1989-09-07 |
| CN1022836C (en) | 1993-11-24 |
| DE68907953D1 (en) | 1993-09-09 |
| EP0331394B1 (en) | 1993-08-04 |
| KR890014554A (en) | 1989-10-24 |
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